Butyl and n-propoxy-z-carbo-
methoxyaminobenzimidazoles

ABSTRACT

1. 5(6)-N-BUTYL-2-CARBOMETHOXYAMINOBENZIMIDAZOLE.

United States Parent Reissued Apr. 29, 1975 28,403 (6)-N-BUTYL ANDN-PROPOXY-Z-CARBO- METHOXYAMINOBENZIMIDAZOLES Philip Paul Actor,Phoenixville, and Joseph Frank Pagano,

Paoli, Pa., assignors to Smithkline Corporation, Philadelphia, Pa.

No Drawing. Original No. 3,682,952, dated Aug. 8, 1972, Ser. No. 48,669,May 19, 1970, which is a division of application Ser. No. 562,117, July1, 1966, now Patent No. 3,574,845, which is a continuation-in-part ofabandoned applications Ser. No. 387,524, Aug. 14, 1964, and Ser. No.516,120, Dec. 23, 1965. Application for reissue July 25, 1973, Ser. No.381,937

Int. Cl. C07d 49/38 US. Cl. 260309.2 2 Claims Matter enclosed in heavybrackets II] appears in the original patent but forms no part of thisreissue specification; matter printed in italics indicates the additionsmade by reissue.

ABSTRACT OF THE DISCLOSURE 5 (6) -n-butyl 0r n-propoxy 2carbomethoxyaminobenzimidazoles having anthelmintic activity areprepared by reacting methylcyanocarbamate with n-butyl ornpropoxy-o-phenylenediamin'e in a suitable organic solvent.

[Anthelmintic compositions comprising esters of benzimidazolyl carbamicacids, and their trio analogs, both of which may be optionallysubstituted on the benzene ring, are disclosed. A process for theirpreparation involves reacting cyanamide in a suitable organic solventwith the appropriate alkyl substituted haloformate to form acyanocarbamate, followed by the addition of an o-phenylenediamine toyield the described anthelmintic agents] This application is a reissueof US. Pat. No. 3,682,952 issued Aug. 8, 1972 from Ser. No. 48,669 filedMay 19, 1970, which is a divisional application of Ser. No. 562,117filed July I, 1966 now U.S. Pat. No. 3,574,845 issued April I 3, 1971,which is a continuation-in-part of Ser. No. 516,120 filed Dec. 23, 1965,now abandoned, and Ser. No. 387,524 filed Aug. 4, 1964, now abandoned.

[This application is a division of our copending application, Ser. No.562,117, filed July 1, 1966, now US. Pat. No. 3,574,845 whichapplication is a continuationin-part of our copending applications. Ser.No. 387,524, filed Aug. 4, 1964 now abandoned, and Ser. No. 516,120,filed Dec. 23, 1965 now abandoned] This invention relates toanthelmintic compositions containing esters of benzimidazolyl carbamicacids, and their 'thio analogs, benzene ring substituted esters, and tometh- Formula I wherein R is a lower alkyl group containing from one tofive carbon atoms, or preferably hydrogen;

R is lower alkyl containing from one to six carbon 7 atoms, cycloalkylincluding alkyl cycloalky containing from three to ten carbon atoms;akenyl straight or branched chain containing from two to ten carbonatoms; phenyl; or naphthyl;

X and X are oxygen or sulfur, with at least one of them being oxygen; Yand Z are hydrogen, alkyl containing from one to fifteen carbon atoms;lower alkoxy containing from one to fifteen carbon atoms,trifiuoromethyl; amino; halogen; preferably chloro or bromo; hydroxy;nitro; lower alkyl thio; alkylamino; dialkylamino; cyano; acylaminocontaining from two to seven carbon atoms; carboxy; carbalkoxycontaining from two to seven atoms; N-alkylcarboxamido; orN,N-dialkylcarboxamido; with the alkyl substituents not specificallydefined having from one to eight carbon atoms.

It is preferred to use as the active ingredient of the 5 novelcompositions of this invention, compounds as shown in Formula 11 below:

Formula II wherein R is lower alkyl containing from one to three carbonatoms; and Y and Z are hydrogen, lower alkyl containing from one toeight carbon atoms; lower alkoxy containing from one to eight carbonatoms; amino; alkylamino or dialkylamino, each alkyl group containingfrom one to four carbon atoms; halogen, preferably chloro; or nitro.

Preferred members of Formula II which are wholly novel compounds arethose where R is cycloalkyl from three to six carbon atoms, phenyl ornaphthyl.

The most advantageous compounds are those of Formula II in which one ofY and Z is lower alkyl containing from one to six carbons, or loweralkoxy containing from one to six carbons, and the other is hydrogen;and R is methyl.

A novel compound within Formula II of exceptional eflicacy is 5(6) nbutyl 2 carbomethoxyaminobenzimidazole, which demonstrates excellentactivity against the mouse pinworm at 10 mg./kg.; against importantsheep nematodes at 5 mg./kg.; and against the migratory stages ofAscaris suum in mice at 0.1% of the diet.

An accidental synthesis of one of the thio compounds of Formula I hasbeen mentioned in the literature but no 'particular pharmacologicalactivity was attributed to it.

Specifically, the synthesis of the compound ethyl N- benzimidazolylthionocarbamate has been reported by Wang et al., I. Am. Chem. Soc., 79,5706 (1957). Similarly, certain compounds of Formula I wherein the R ishydrogen and the Xs are both oxygen are known, but no anthelminticactivity has been suggested for them (US. Pat. Nos. 2,933,502 and3,010,968).

Examples of specific compounds falling within Formula I are:

Methyl 2-benzimidazolyl carbamate Methyl Z-benzimadazolylthionocarbamate Ethyl Z-benzimidazolyl carbamate Ethyl 2-benzimidazolylthionocarbamate 2-Benzimidazolylthiocarbamic acid, S-ethyl ester PropylZ-benzimidazolyl carbamate Propyl Z-benzimidazolyl thionocarbamateIsopropyl 2-benzimidazolyl thionocarbamate Butyl 2-benzimidazolylcarbamate Butyl 2-benzimidazclyl thionocarbamate Isobutyl2-benzimidazolyl carbamate sec-Butyl Z-benzimidazolyl carbamate Pentyl2-benzimidazolyl carbamate Isopentyl Z-benzimidazolyl carbamate HexylZ-benzimidazolyl carbamate 4(7)-Methyl-2-carbomethoxyaminobenzimidazole6-)-Methoxy-Z-carbomethoxyaminobenzifiiidaiole' 4 (7-Trifluoromethyl-2-carbomethoxyaminobenzimidazole 5 (6)-Amino-2-carboethoxyaminobenzimidazole 4( 7-Chloro-2-carboethoxyaminobenzimidazole 5 (6-Hy'clroxy-2-carboethyoxyaminobenzimidazole 4(7) -Nitro-2carboethoxyaminobenzimidazole 5 6)-Methylthio-Z-carboethoxyaminobenzimidazole2-Carbovinyloxyaminobenzimidazole 2-Carboethynyloxyaminobenzimidazole2-Carboallyloxyaminobenzimidazole 2-Carbomethallyloxyaminobenzimidazole2-CarbodimethallyloxyaminobenzimidazoleZ-Carbopropargyloxyaminobenzimidazole 2-Carbopheny1oxyaminobenzimidazole2-CarbonaphthyloxyaminobenzimidazoleZ-CarbocyclopropyloxyaminobenzimidazoleZ-Carbo-l-methylcyelopropyloxyaminobenzimidazole2-Carbocyclobutyloxyaminobenzimidazole2-Carbocyclopentyloxyaminobenzimidazole2-Carbocyclohexyloxyaminobenzimidazole 4(7)-Methyl-2carbovinyloxyaminobenzimidazole 5 6-Methoxy-2-carboallyloxyaminobenzimidazole4(7)-Trifluoromethyl-2-carbomethallyloxyaminobenzimidazole 4 6)-Amino-Z-carbodimethylallyloxyaminobenimidazole 4 (7-Chloro-2-carbopropargyloxyaminobenzimidazole' 5 (6-Hydroxy-2-carbobutynoxyaminobenzimidazole '4 (7-Nitro-2-carbopentynoxyaminobenzimidazole 5 (6)-Methylthio-2,2-carbohexynoxyaminobenzimidazole 4 (7 -Bromo-2-carboallyloxyaminobenzimidazole 5 6)-Chloro-2-carboallyloxyannnobenzimidazole 4( 7-Ethoxy-2-carboallyloxyaminobenzimidazole 56)-Methoxy-2-carboallyloxyaminobenzimidazole 4 (7-Nitro-2-carboallyloxyaminobenzimidazole 5 (6-Methyl-2-carboallyloxyaminobenzimidazole 4(7)-Trifluoromethyl-2-carboallyloxyaminobenzimidazole 5 (6-Amino-2-carboallyloxyaminobenzimidazole 4.( 7-Hydroxy-2-carboallyloxyaminobenzimidazole 5 6)-Chloro-2-carbornethoxyaminobenzimidazole 5 (6)-Amino-2-carbomethoxyaminobenzimidazole 5 (6)-Dirnethylamino-Z-carbomethoxyaminobenzimidazole 5 6)-Methyl-2-carbomethoxyaminobenzimidazole 4(7)-Ethyl-2-carbomethoxyaminobenzimidazole 5 6)-n-Propyl-2-carbomethoxyaminobenzimidazole 5 (6 )-n-B utyl-Z-carbomethoxyaminobenzimid azole 5 (6-Methoxy-2-carbomethoxyaminobenzimidazole 4 (7) -Ethoxy-2-carbomethoxyarninobenzimidazole 5 (6 -n-Prop oxy-2-carbomethoxyaminobenzirnid azole 4 (7-n-Butoxy-2-carbomethoxyaminobenzimidazole 5 (6 -n-Pentyl-2-carbomethoxyaminobenzimidazole 5,6-Dimethyl-2-carbomethoxyaminobenzimidazole5 (6 -Nitro-2-carbomethoxyaminobenzimidazole 5 6 -n-Pentyl-2-carbomethoxyaminobenzimidazole' 5 6) -Isopentyl-Z-carbomethoxyaminobenzimidazole5 (6 )-sec-Butyl-2-carbomethoxyaminobenzimidazole 5 6)-Isobutyl-2-carbomethoxyaminobenzimidazole 5(6)-n-Hexyl-2-carbomethoxyaminobenzimidazole 5 6)-n-Heptyl-2-carbomethoxyaminobenzimidazole 5 (6-n-Octyl-2-carbomethoxyaminobenzimidazole or l-optical isomers, as wellas racemic mixtures of these isomers.

If desired, the isomers may be separated for individual use byresolution methods known to the art, such as fractional crystallizationof the l-tartrate salts of the carbamates. Alternatively, a synthesisstarting with an optically active side chain may yield the desiredoptical isomer.

The compounds of Formula I being weak bases will normally form saltswith inorganic and organic acids. Accordingly, the nontoxic salts formedwith pharmaceutically acceptable strong inorganic and organic acids maybe alternatively employed in the compositions of the invention. Othernontoxic molecular complexes known to exist that can be derived fromcompounds of Formula I may also be used in this invention, since theanthelr'nintic acivity rests in the benzimidazolyl carbamic acidstructure itself.

The compounds of Formula I in which R is hydrogen, X is sulfur, and X isoxygen, are prepared by reacting appropriately substitutedZ-aminobenzimidazoles with carbon disulfide and an appropriate alcoholto give the corresponding ester of benzimidazolyl thionocarbamic acid byrefluxing the reaction mixture on a steam bath.

In the case of the compounds of Formula I'in which R is lower alkyl, Xis sulfur, and X is oxygen, these may advantageously be prepared by thesame general procedure, starting with an appropriately substituted2-aminobenzimidazole having a lower alkyl grouping on the 1- position.

The compound of Formula I in which R is hydrogen R is lower alkyl, X isoxygen, and X is sulfur, are prepared from the correspondingappropriately strongly substituted lower alkyl N-benzimidazolylthionocarbamate by treatment thereof with an alkyl halide in a suitablesolvent.

The compounds of Formula I in which R is hydrogen and both X and X areoxygen, are prepared by reacting cyanamide in a suitable organicsolvent, such as pyridine, with the appropriate R substitutedhaloformate to form a cyanocarbamate, followed by the addition of anophenylenediamine to give the corresponding ester of a benzimidazolylcarbamic acid. Thus, these compounds are readily synthesized by priorart methods.

The haloformate reactant can be a chloroformate or a bromoformate, thechloroformate being preferred for reasons of availability and cost. Thechoice of the R substituted haloformate is of course dependent upon theparticular ester product desired.

More specifically, one to two molar equivalents of an o-phenylenediamineare added slowly to a solution of the cyanocarbamate and the reactionmixture either heated at steam bath temperature for 1-4 hours or allowedto stand at room temperature for a longer period of time, up to 24hours. Heating for about 3 hours, following reaction at room temperaturefor an equal period of time is preferred.

The o-phenylenediamine reactant can have substituents on the benzenering which correspond to Y and Z as defined in Formula I. The resultingbenzimidazoles hear these substituents at the corresponding position ofthe benzene ring. The nature of the condensation reaction is such thatit is generally applicable to o-phenylenediamines, regardless of thesubstituents which may appear on the benzene ring. I

An alternative process for making the anthelmintio compounds of thisinvention starts with an S-lower alkyl pseudothiourea sulfate. Thissulfate is treated with one benzene. This intermediate is reduced withtin chloride to give the corresponding p-aminoalkylbenzene, followed bynitration in mineral acid medium with amyl nitrate to give ano-nitro-p-alkylaniline. This latter intermediate is again reduced withtin chloride to yield a lower alkyl substituted o-phenylenediamine. Thediamine intermediate is converted by the afore-discussed thioureasulfate process to the appropriate lower alkyl substitutedbenzimidazole- Z-carbamic acid, alkyl ester.

The compounds of Formula II in which R is alkyl and Y is dialkylaminoand Z is hydrogen, can be prepared starting with a dialkylaminobenzene,and following the above-described sequence of steps to yield thedialkylamino substituted benzimidazole-2-carbamic acid, alkyl ester.

The compounds of Formula II wherein R is lower alkyl, Y is alkylaminoand Z is hydrogen, are prepared starting with 3,4-dinitroaniline. Thedinitro compound is treated with, for example, butyryl chloride to yield1- butyramido-3,4-dinitrobenzene, which is reduced with lithium aluminumhydride to yield 1-butylamino-3,4-diaminobenzene. This triaminobenzeneis converted to the corresponding benzimidazole-Z-carbamic acid, alkylester, by the afore-discussed thiourea method.

The compounds of Formula II wherein R' is lower alkyl, Y is alkoxy, andZ is hydrogen, are prepared starting with 4-hydroxyacetanilide. Theanilide is treated with the appropriate alkyl bromide and an alkalimetal hydroxide, to yield the corresponding p-alkoxylacetanilide,according to the procedure of Buu-Hoi et al., J. Chem. Soc., 1955, 1573.The substituted compound is nitrated with red fuming nitric acid, whilesuspended in glacial acetic acid and acetic anhydride at about 0 C. Theresulting o-nitro-p-alkoxyacetanilide is collected, and isrecrystallized from methanol. This disubstituted acetanilide is thendeacylated by refluxing with an alkali metal hydroxide in ethanol, withthe disubstituted aniline being recovered from acidified Water. Thedisubstituted aniline is then hydrogenated at 50-80 p.s.i. in benzene,with removal of the solvent by distillation, yielding the correspondingdiamine. This diamine intermediate is converted by either of the aforediscussed cyanamide or thiourea sulfate processes to the appropriatelower alkoxy substituted benzimidazole-Z-carbamic acid, alkyl ester.

The compounds of Formula II werein R is lower alkyl, and Y and Z arealkoxy, are prepared starting with o-dihydroxybenzene. The benzene istreated with the appropriate alkyl bromide, and an alkali metalhydroxide in ethanol, to yield the corresponding o-dialkoxybenzene. Thesubstituted compound is nitrated with nitric acid while suspended inacetic acid, to yield 1,2-dialkoxy-4,5- dinitro benzene (J. Proc. Roy.Soc., N. S. Wales, 71, 103-11 (1938)), followed by hydrogenation to givethe corresponding substituted diamine. The diamine is converted, aspreviously described, to a 5,6-dialkoxybenzimidazole-Z-carbamic acid,alkyl ester.

The benzimidazolyl carbamates of Formula I have been found to possessuseful anthelmintic properties, that is, broad spectrum activity againstparasites of warm blooded animals, including both mature and immatureparasitic forms. In particular, these compounds have been found toexhibit high activity against various helmintic infections of theintestinal tract of economically important animals, coupled with lowsystemic toxicity to the host animal.

For example, the disclosed compounds are generally effective in clearingmice of worm infections for laboratory purposes, among others: Syphaciaobvelata and Aspicularis tetraptera (mouse pinworm), Nematospiroidesdubius (mouse hookworm), and the migratory stages of Ascaris suum.

Other susceptible helminths include Toxocara canis, found in naturallyinfested dogs. Also, parasitic to this host are Ancylostoma canium,Trichuris vulpis (whipworm), and Physalaptera spp.

Compounds of Formula II have been demonstrated as efficacious againstparasites of pigs, such as the migratory 6 stages of Ascaris suum, thuspreventing the development of verminous pneumonia.

Compounds of Formula I have also been demonstrated as eflicaciousagainst parasitic gastroenteritis in sheep, such as Haemonchuscontortus, Ostertagia spp., Trichostrongylus spp., Nematodirus spp.,Trichuris ovis, Cooperia spp., and Strongyloides papillosus. Bunostomumtrigonocephalum and Oesophagostornum spp., are other important parasitesof sheep.

Animals of low weight are treated with unit doses ranging no higher thana few milligrams; whereas animals of high body weight, such asruminants, require proportionately larger unit doses ranging up toseveral grams. Preferably, a single dose is administered daily for eachanimal species based on the weight of that species.

The amount of ingredient administered will depend on the weight of thehost, but will usually be between about 1 mg./kg. and 500 mg./kg. ofbody weight daily.

For example, ethyl-N-benzirnidazolyl thionocarbamate at an oral dailydose of 25 mg./kg. tested in clearing mice of natural pinworm infection,following generally the method of McCowen et al., reported in theAmerican Journal of Tropical Medicine, 6, 894 (1957), gave a 45% resultin terms of worms cleared; while a 400 mg./kg. dose gave 98%. Its LD inmice is in excess of 1 g./kg.

Ethyl 2-benzimidazolyl carbamate at an oral daily dose of 50 and 250mg./ kg. for three days, tested in clearing mice of natural pinworminfection, gave 73% and 100% clearance, respectively. Additionally, thissame compound, given at a daily dosage of 0.05% and 0.20% of diet for 5days, against mouse hookworm infection (0.2% of diet approximates 100mg./kg. of body weight, based on 20 gram mouse) gave a 65% and 100%reduction in the worm burden, respectively.

2-Carboallyloxyaminobenzimidazole at an oral daily dose of 10 mg./kg.tested in clearing mice of natural pinworm infection, followinggenerally the method of McCowen et al., gave a 69.7% 1 result in termsof worms cleared; while at a dose of 50 and 250 mg./kg. for three days,tested in clearing mice of natural pinworm infection, it gave 74.9% and100% clearance, respectively.

In the same procedure against pinworm 5-chloro-2-carbomethoxyaminobenzimidazole, at an oral daily dose of 10 and 50mg./kg. gave 55% 1 and 59% clearance, respectively.

Typical daily dosage in dogs will run from about 25- 200 mg./kg.(preferably 100 25 mg), given orally.

In dogs, naturally infested with various gastrointestinal helminths,ethyl 2-benzimidazolyl carbamate was particularly effective againstTrichuris vulpis. At 100 mg./kg. of body weight the test compound causeda percent reduction ranging from zero up to 100%, in five dogs, with anaverage of 41% as determined by the number of helminths expelled invoided feces, as compared to the number of T. vulpis surviving anautopsy.

In lambs, naturally infested with various gastrointestinal nematodes,three of the compounds of Formula I were each tested at 100 mg./kg. ofbody weight (B.W.), in a single dose of 10% concentration in city water,with the impressive results given in the tabulation below:

In lambs, naturally infested with various gastrointestinal nematodes,three of the compounds of Formula I, (formulated per Example 16) wereeach tested at the indicated dosages in mg./kg. of body weight (B.W.),in

1 Figure is average of two experiments.

a single dose of 1% concentration in city water, with the strikingresults given in the tabulation below:

5(6)-methoxy-Z-carbomethoxyarninobenzirnidazole (15 mg. 'g.).

Identification of helminths by examination of the feces of the lambs,both preand post-treatment, in terms of eggs per gram, and also atautopsy, verified that the tabulated compounds were highly activeagainst almost all the sheep helminths enumerated previously. The namedmethyl compound was also active against Trichuris at 100 mg./kg. B.W.The named allyl compound was quite active against Haemonchus,Strongyloides and Trichuris at 12.5 mg./kg. B.W.

In practice, a pharmacologically active compound of structural Formula Iis usually formulated with a nontoxic carrier therefore to giveanthelmintic compositions of this invention. The carrier may be anorally ingestible container for the active ingredient, for example, ahard or soft gelatin capsule; or it may be a pharmaceutically acceptablediluent or excipient of the kind normally used in the production ofmedicaments, ready for use, for example maize starch, terra alba,lactose, sucrose, calcium phosphate, gelatin, talcum, stearic acid,magnesium stearate, dextrin, agar, pectin or acacia.

Exemplary of liquid carriers are peanut oil, olive oil, sesame oil, andwater. Similarly, the carrier or diluent may include a time delaymaterial such as glyceryl monostearate or glyceryl distearate alone orwith a Wax.

A wide variety of pharmaceutical forms can be employed. Thus, if a solidcarrier is used, the preparation can be tableted, placed in a hardgelatin capsule, or compounded in the form of a troche or lozenge. Theamount of solid carrier will vary widely but preferably will be fromabout 25 mg. to about 3 gm. If a liquid carrier is used, the preparationmay be in the form of a soft gelatin capsule, placed in an ampule or inliquid suspension.

The compositions are most often made up in a form suitable for internaladministration and may therefore take the form of a liquid, for example,an emulsion or a sterile solution or suspension in Water, oil, such asarachis oil, or other liquid.

The compositions are advantageously made up in a dosage unit formadapted for the desired mode of administration. Thus, for the preferredoral administration, the dosage unit may take the form of a suspension,tablet, packaged powder, bolus, or encapsulated powder. The quantity ofactive ingredient in each dosage unit Will be such that one or moreunits are required for each therapeutic administration.

As previously mentioned, the compounds of Formula I have generalanthelmintic activity and accordingly a further and most importantaspect of this invention provides a method of treating hehninticinfections in an animal which comp-rises administering, usually orally,to the animal in a sufficient nontoxic, but effective dose, ananthelmintic compound falling within the definition of Formula I,generally in the form of a pharmaceutical or veterinary composition ashereinbefore described. The daily dose range commonly used is from about1 mg./kg. to about 500 mg./ kg. depending on the species of host andregimen used. One dose per day administration is preferred but up tofive of the dosage units described above may be used if desired.

Where tableting is used, the resulting tablets are then coated withmethyl methacrylate to form an enteric coating, i.e. a coating which issubstantially insoluble in gastric secretion but substantially solublein intestinal fluids.

It will be appreciated that the active ingredient used in theformulation of the tablets described above may be replaced with othercompounds of Formula I having the necessary anthelmintic activity.Furthermore, other materials may be used to form the enteric coating,for example other synthetic plastic materials such as methyl acrylate,cellulose derivatives, hydrogenated caster oil or phthalates.

The compositions thusly prepared are administered, usually orally, to aninfected host from 1-5 times daily for anthelmintic activity.

The following examples illustrate syntheses which may be employed informulating the compositions of the invention but are not consideredlimiting the invention described herebefore.

EXAMPLE 1 Preparation of ethyl 2-benzimidazolyl thionocarbamate Amixture of 13.3 g. of Z-aminobenzimidazole, 50 ml. of carbon disulfide,and 30 ml. of absolute ethanol is refluxed for 50 hours. The product isseparated by filtration and purified by recrystallization from absoluteethanol.

EXAMPLE 2 Preparation of 2-benzimidazolyl-thionocarbamic acid, S-ethylester Three g. of ethyl 2-benzimidazolyl thionocarbamate, 4.5 ml. ofethyl iodide, and 9 ml. of dimethylformamide were mixed and stirred for3.5 hours, at the end of which time a clear, yellow solution waspresent. Acetone (25 ml.) was added and evaporated at room temperature,the acetone addition and evaporation steps Were repeated. Water (20 ml.)was added, which precipitated a white solid. The solid was collected(1.1 g.), washed with water, and dried in vacuo, over P 0 The entireproduct was recrystallized twice by dissolution in a minimum amount ofcold glacial acetic acid, followed by Water addition to initiaterecrystallization. A slight opalescent appearance required charcoalingand filtration.

The crude product was again dissolved in minimal glacial acetic acid,and water added, while being maintained at 0 C. A white solid formed,which was collected, washed with water, and dried overnight, in vacuo,over P 0 yielding a purified sample 320-323" C. (dec.).

The structure was confirmed based on the analytical data' and spectra.

EXAMPLE 3 Preparation of ethyl 2-benzimidazolyl carbamate Cyanamide (2.1g.) was added to 40 ml. of pyridine. Ethyl chloroformate (4.78 ml.) wasthen added dropwise, while the temperature was maintained at about 0 C.The reaction mixture was stirred for 10 minutes at this temperature, andthen at room temperature for an additional 20 minutes.

O-Phenylenediamine (10.8 g.) was added and the mixture was allowed tostand at room temperature for three hours,- then heated three hours onthe steam-bath. The mixture was cooled to about 0 C., with the solidthat formed being collected, washed with cold pyridine, dissolved inaqueous-ethanolic alkali, filtered, and the product precipitated byadding acetic acid. The material had m.p. 33033l C. (dec.). Similarly,the melting points in Examples 4 to 7 are assumed to be of thedecomposition products.

EXAMPLE 4 Preparation of methyl 2-benzimidazolyl carbamate Using theprocedure detailed in Example 3, 3.98 g. of cyanamide, 8193 g. ofmethylchloroformate, and 20.52 g. of o-phenylenediamine, are reacted togive 2.44 g. of crude product, m.p.,-313-315 C. Two recrystallizationsfrom 9 glacial acetic acid, yielded a purified product of 1.3 g., mp.320-322 C., whose structure was confirmed by elemental analyses andspectral data.

EXAMPLE 5 Preparation of propyl 2-benzimidazolyl carbamate Using theprocedure described in Example 3, the desired product may be preparedfrom n-propyl chloroformate, Cyanamide, and o-phenylenediamine.

EXAMPLE 6 Preparation of butyl 2-benzimidazolyl carbamate Using theprocedure of the foregoing examples, 6 g. of cyanamide, 19.04 g. ofn-butyl chloroformate, and 30.24 g. of o-phenylenediamine, are reactedto give crude product (7.93 g.) m.p. 266268 C. Two recrystallizationsfrom ethanol gave 3.68 g. of solids which were dried in vacuo over Pyielded a dried product, whose structure was confirmed by elementalanalyses and spectral data.

EXAMPLE 7 Preparation of isobutyl Z-benzimidazolyl carbamate Using theprocedure of the foregoing examples, 6 g. of cyanarnide, 19.04 g. ofisobutyl chloroformate, and 30.24 g. of o-phenylenediamine are reactedto give a crude product (2 g.) m.p. about 170 C.

Two recrystallizations from methanol, give 0.341 g. of a solid, whichwas dried, in vacuo, over P 0 yielding dried product, whose structurewas confirmed by elemental analyses and spectral data.

EXAMPLE 8 Typical Cattle Bolus Containing an Anthelmintic DescribedHerein Grams Ethyl 2-benzimidazolyl thionocarbamate 2.0 Calciumphosphate 2.5 Maize starch 0.54 Talcum 0.14 Gum arabic 0.15 Magnesiumstearate 0.05

The calcium phosphate and the anthelmintic compound are thoroughlymixed, and the mixture reduced to a particle size finer than 60 mesh.About one-half of the starch is added, as an aqueous paste, and theresulting mixture granulated. The granules are passed through a #10 meshscreen and dried at 110-130 F. for about 8 hours. The dried materialsthen passed through a #16 mesh screen. The guar gum and the balance ofthe starch are added and the mixture thoroughly blended. Finally, theremainder of the ingredients are added and the entire mass thoroughlymixed and compressed into a bolus. The magnesium stearate, talcum andgum acacia are of a particle size to pass a #10 mesh screen.

EXAMPLE 9 Typical Sheep Drench Containing an Ant-helmintic DescribedHerein Parts by Weight Ethyl Z-benzimidazolyl carbamate 60 Terra AlbaEnglish 35.5 Tragacanth, U.S.P. 3.0 Sodium Lauryl Sulfate 1.5 Water.

The above solid components are thoroughly mixed, giving a waterdispersable power. This powder can be directly admixed with water inconcentrations on the order of 5 g. of powder to 5 cc. of water.

I EXAMPLE 10 Preparation of substituted 2-carbalkoxyaminobenzimidazolesWhen the following substituted o-phenyleuediamines are substituted forthe o-phenylen'ediaminedn the procedure of Example 4, the correspondinglisted products are obtained:

Starting material Product 3-brorno-o-phenylenediamine-4(7)-bromo-2-carbomethoxyamlno benzimidaz e.3-ethoxy-o-phenylenediamine- 4(7)-ethoxy2earbomethoxyamiuo=benzimidazole. 3-nitro-o-phenylenediamine4(7)-nitro-2-earbomethoxyaminobenzimidazoS-trifluoromethyl-o-phenylenedi- 4(7)-trifluoromethyl-2-earbomethoxyamine. aminobenzimidazole. i-amino-o-phenyleuediamine5(6)-amino-2-earbomethoxyaminobenzimidazole. j3-hydroxy-o-phenylenediamine4(7)-hydroxy-2earbomethoxyaminobenzirnidazole.

EXAMPLE ll Novel Sheep Drench Containing an Anthelmintic Carbamate Partsby Weight Methyl 2-benzimidazolyl carbamate 60 Terra Alba English 16Methyl cellulose l Polethylene glycol (Methocel 4000) 20 Antifoam AF 3Silicone emulsion supplied by Dow Chemical Co. The above ingredients aresuspended, one part powdered mixture to four parts water, and spraydried as is well known in the art.

EXAMPLE 12 Novel Sheep Drench Containing an Anthelmintio' CarbamateEthyl 2-benzimidazolyl carbamate, l0 grants. 0.1 N HCl solution, quantumsufiicient to make 1 liter.

' chloroformate 2 (11.47 g.) is then added dropwise, while thetemperature is maintained at about 0 C. The reaction mixture is stirredfor 10 minutes at this temperature, and then at room temperature for anadditional 20 minutes.

O-Phenylenediamine (20.56 g.) is added with stirring and the mixture isallowed to stand at room temperature for one hour, then is heated twohours on the steam bath, followed by the addition of 240 ml. of H 0. Themixture is cooled to about 0 C., with the solid that formed beingcollected by suction filtration, and air dried. The material had a ma).(fast heat) about 300 C. It is recrystallized once from 225ml. ethanol,then twice from cold absolute ethanol, which will not raise the meltingpoint of the sample. The purity and structure of the product areconfirmed by thin layer chromatography, elemental analyses and spectraldata.

EXAMPLE 14 Preparation of substituted Z-carballyloxyamino- Ibenzimidazoles When the following substituted o-phenylenediamines aresubstituted for the o-phenylenediamine in the proce- Available fromOhemetron Corp., Chicago, 111.

fl-tiifluoromethyl-o-phenyleneallyloxyaminobenzimidazole.

diarnine.

4-amino-o-phenylenedlamine 5(6)-amino-2-carboallyloxyaminobenzimidazole.3-hydroxy-ophenylenediamine4(7)-hydroxy-2-carboallyloxyaminobenzimidazole.

EXAMPLE 15 When the following haloformates are substituted for the allylchloroformate in the procedure of Example 13, the corresponding listedproducts are obtained:

Starting material Product Z-Methallylchloroi'ormate2-carbometha1lyloxyamino- (C.A. 46'8417, g benzimidazoleVinylchloroiormateTuS. Patent 2-carblovinyloxyaminobenzimidazo eCyanamide (18.6 g.0.444 moles), dried in vacuo over P is dissolved in225 ml. dry pyridine and is chilled in an ice bath. The solution isstirred continuously as 34.2 ml. (42 g.==0.444 moles) ofmethylchloroformate is added fairly slowly, keeping the temperaturebelow 26". C. The solution is stirred in an ice bath for minutesafterthe addition is completed, and then at room temperature for 1 hour.4-Chloro-o-phenylenediamine (63.6 g.0. 444. moles) is added. The darkred solution is stirred at room temperature for /2 hour, and is heatedon the steam bath for 5 hours.

The pyridine is evaporated with stirring at 50. C., and the resultantslurry of black oil and solid is mixed with 300 ml. ethanol, warmedslightly, and stirred until. all of the black oily liquid dissolves.Only crystalline material is left undissolved. Water (100 ml.) is addedand the pyridine is filtered off, washed with ethanol and driedovernight on a porous plate. Crude yield is 13.3 -g. (.059 moles). Theproduct is suspended in 400 ml. of ethanol:water, then ml. of 2.5 NaOHis added. The solution turns black, and almost all of the solid willdissolve. The insoluble material is filtered off and the pH of thesolution is adjusted to 7.5 using glacial acetic acid. A light greysolid appears. It is collected, washed (Yield: 10.2 g.)

The product is further purified by dissolving in dimethylsulfoxide at100 C., filtering the dark solution and add- 12 is light tan colored anddecomposes with melting at 295- 300 C. In order to get rid of residualdimethylsulfoxide, the solid product is stirred with boiling Watertwice, and then filtered off. It is dried at 25 C. in vacuo over P 0 Thestructure is confirmed by elemental analyses and spectral data.

EXAMPLE 17 Typical Cattle Bolus Containing an Anthelmintie DescribedHerein Grams 2-Carboallyloxyaminobenzimidazole 2.0 Calcium phosphate 2.5Maize starch 0.54 Talcum 0.14 Gum arabic 0.15 Magnesium stearate 0.05

The calcium phosphate and the anthelmintic compound are thoroughlymixed, and the mixture reduced to a particle size finer than 60 mesh.About one-half of the starch is added, as an aqueous paste, and theresulting mixture granulated. The granules are passed through a #10 meshscreen and dried at 130 F. for about 8 hours. The dried materials thenpass through a #16 mesh screen. The guar gum and the balance of thestarch are added and the mixture thoroughly blended. Finally, theremainder of the ingredients are added and the entire mass throughlymixed and compressed into a bolus. The magnesium stearate, talcum andgum acacia are of a particle size to pass a #10 mesh screen.

EXAMPLE 18 The above solid components are thoroughly mixed, giving awater dispersable powder. This powder can be directly admixed with waterin concentrations on the order of 5 g. of'powder to 5 cc. of water.

EXAMPLE l9 Novel Sheep Drench Containing an Anthelmintic Carhamate Partsby Weight 5(6)-n-Butyl-2-carbomethoxyaminobenzimidazole 80.0 Atmos 3005.0 Starch, U.S.P. 12.0 Tragacanth, U.S.P. 3.0 Water Q.s.

Mono and diglycerides of fatformin fatt acids su lied by Atlas Chemical.g y pp The above solid components are thoroughly mixed, giving awater'dispersable powder. This powder can be directly admixed with waterin concentrations on the order of 5 g. of powder to 5 cc. of water.

EXAMPLE 20 70. with 50% aqueous ethanol, and dried on porous plate.

ing an equal volume of hot methanol. The final precipitate 75 NovelSheep Drench Containing an Anthelmintic Carbamate2-Carboallyloxyaminobenzimidazole, 10 grams. 0.1 N HCl solution, quantumsufiicit to make 1 liter.

Preparation of 5-methyl-2-carbomethoxyamino benzimidazole Dry cyanamide(20.6 g.0.488' moles) is dissolved in 250 ml. of dry pyridine and ischilled in an ice bath. Methyl chloroformate (46.1 g.) is added over a20-minute period, stirred for. 10 minutes in an ice bath, then at roomtemperature for 1.5 hours. 3,4-Toluene diarnine (59.8 g. 0.488 mole) isadded in one portion forming a deepwine red solution. The solution-isstirred at room temperature for 40 minutes, and heated on a steam bathfor 2 /z hours,-then is left at room temperature overnight. v Almost allofthe pyridine is evaporated in vacuo and the orange residue issuspended in 700ml. of 50% aqueous ethanol,- to which is added 250 ml.of 2.5 N sodium hydroxide. Any undissolved solid is filtered 01f. Thevery dark filtrate is adjusted to a pH of about 7.5 using glacial aceticacid, and the precipitated crude product is collected, washed, and driedovernight on porous plates in a steam oven. t

. Twelve g. of crude product are dissolved in 170 ml. ofdimethylsulfoxide (DMSO) at 100-l05 C., forming a dark solution, whichis filtered, diluted with 190 ml. of 28 ethanol. A precipitate forms,which is chilled quickly, and is put in a freezer.

it Another 15.9 g. of crude product is dissolved in 200 ml. of DMSO of100-105 C., which is filtered, and diluted with 180 ml. of hot ethanol.The solution is cooled quickly, stored in a freezer.

The products are collected, combined and washed with 2B ethanol,yielding 13.0 g. of a slightly off-white product, which is resuspendedin 500 ml. of boiling hot water and with stirring, filter, resuspendedin fresh water. The procedure is repeated yielding a product which isthen dried in vacuo over P having a m.p. 297-303 C. (d.).

The structure is confirmed by elemental analyses and spectral data. 1 r

EXAMPLE 22 5n-butyl-2-carbomethoxyamino-' 7 Preparation of benzimidazoleequipped with a mechanical stirrer; addition funnel, and

thermometer, 13.9 g. (0.05 moles) of 2-m'ethyl-2-thiopseudoureasulfatein about ml. of water is stirred in an ice bath. Methylchloroformate(9.45 g.0.1 moles) is added at one time. The; mixture is stirred at 0C., for ten minutes, then a total of 19 ml. of sodium hydroxide is addedover ten minutes while maintaining the temperature-below 20 C. j e

At this point the pH is about 8 and remains there after 5 minutes ofstirring. Ten ml. of acetic acid is added, making the pH about 5 andkeeping the temperature about 20 C. t

- A solution of 4-n-butyl-o-phenylenediamine ethanol, the hydrochloride,is

prepared-from 11.9 g. (0.05 mole) of added to the reaction mixture. 1

The addition funnel is replaced by a condenser, attached to three trapsfor methyl .mercaptan, one empty and two with 10% aqueous NaOI-I. Heatis applied very slowly to the stirred mixture, with gas evolvingconstantly." As the temperature rises slowly, ethanol is added, to con-"trol foaming. The total'reflux time is about of an hour. to roomtemperature and left over" The reaction is cooled the week-end.

A light tan solid is suspended in 50% aqueous ethanol, and recollectedlsolid is dried on a porous plate in an oven.

Ihe product is recrystallized from 1200 to 1400 ml.

collected, washed with water, then The '14 of 30-ethanol plus '150 ml.of water, and is left in a refrigerator overnight. The product iscollected and washed twice with 20% aqueous ethanol.

The product is then recrystallized again from 20% aqueous ethanol. It isdried in vacuo over P 0 to give pure product, m.p. 2257 C. (d.).

The structure is confirmed by elemental analysis and spectral data.

EXAMPLE 23 Preparation of 5,6-dimethyl-2-carbornethoxyaminobenzimidazoleUsing a 1-liter B-necked, round-bottomed flask, equipped with mechanicalstirrer, addition funnel, and thermometer, 20.4 g. (0.0735 moles) of2-methyl-2-thiopseudourea sulfate in 10 ml. of water, is stirred andmaintained at 0 C. Methylchloroformate (13.9 g..147 moles) is added allat once, followed by the addition of about 40 ml. of 25 aqueous sodiumhydroxide, which is added dropwise keeping the temperature about 15 C.and the pH about 6.

At 15 C., 18 ml. glacial acetic acid is added dropwise over about 5minutes reducing the pH to between 5 and 6.

Ten g. (.0735 mole) of comminuted 4,5-dimethyl-ophenylene-diamine isadded all at once to the reaction mixture, followed by 20 ml. of water.

A condenser replaces the funnel, and the gas outlet on the condenser isattached to a series of three traps. Two traps containing about 10%sodium hydroxide. Heat is applied very slowly, and as the temperaturerises gas evolves. Ethanol is added to maintain stirrability. Afterone-half hour at 95 C., the reaction mixture is further diluted withwater and cooled. The pasty mixture is filtered, washed with water,followed by washing with an ethanohwater mixture, and then stirred intoan ethanol: Water mixture. It is recollected, and dried overnight on aporous plate.

The product (13.3 g.) is recrystallized from 350 ml. DMSO plus 320 ml.of ethanol, and left in a refrigerator overnight. Crystals arecollected, Washed with cold ethanol, and air-dried. The solid product isboiled twice with 250 ml. of water, collected, air-dried, and dried at25 C. in vacuo over P 0 to give pure product, having a mp. of 295-305 C.(d.).

The structure is confirmed by elemental analysis and spectral data.

EXAMPLE 24 Preparation of 5-methoxy-Z-carbomethoxyamidobenzimidazole Ina 500 ml. 3-necked round-bottomed flask, equipped with a thermometer,mechanical stirrer, and dropping funnel, 19.8 g. (0.1 moles) of2-methyl-2-thiopseudourea sulfate is stirred into 9 ml. of water. It iscooled to about 5 C., and methylchloroformate is added in one portion.The mixture is stirred at 10-15 C., then 21.4 ml. of 25 aqueous sodiumhydroxide is added drop-wise over about v. tion mixture.

' until it is heated to about 102 C.

After one-half hour at -102 C., the resulting salmoncolored mixture iscooled, stoppered, and left at room temperature overnight.

When water is added to the reaction mixture, a pinkishwhite solid formswhich is collected, washed with water, and then 60% ethanol in watermixture, to yield a'white solid product. The product is again slurriedin 200 ml. of ethanol-water (60:40), collected, and is dried on a porousplate.

The product is recrystallized from 1300 m1. 30-ethanol plus 200 ml. ofwater. Following filtering, recrystallization occurs spontaneously, andit is left in the refrigerator overnight. Y

The crystals are collected, washed in 1:1 mixture of ethanol-water,giving a product, which is dried at 25 C. in vacuo over P The product isagain recrystallized, from 1500 ml. of ethanol plus 100 ml. of water,collected, and washed with 60-40 mixture of ethanol-water and dried at25 C.'in vacuo over P 0 yielding the pure product, having an M.P. of 235C. (d.).

EXAMPLE 25 Preparation of S-nitro-2-carbomethoxyaminobenzimidazole To12.4 g. (0.163 mole of thiourea in 6.2 ml. of water, is added, dropwise,14 g. (0.11 mole) of dimethyl sulfate with stirring. The mixture becomeswarm and colorless, and is refluxed gently for 30 minutes, during whichtime a white crystalline solid appears. The reaction mixture is thencooled at 2 C., yielding 2-methyl-2-thiopseudourea sulfate.

Methylchloroformate (30.8 g.0.326 moles) is added in one portion to thesulfate. To this mixture is added about 75 ml. of 25% aqueous sodiumhydroxide, at a rate which maintains the temperature no higher than l5--C., with the resulting pH of about 7. To this mixture is slowly added 17ml. of glacial acetic acid.

4-Nitro-o-phenylenediamine (25.0 g.0.163 mole) added in one portion,followed by 60 ml. of 30% aqueous ethanol.

Three mercaptan traps are connected to the condenser on the reactionflask, one empty, and two with aqueous sodium hydroxide. The reactionmixture is heated slowly, being brought to reflux at 91 C., for onehour,

after which time the mixture is cooled and filtered. The

precipitate is washed with water and 30% cold aqueous" The structure isconfirmed by elemental analysisand spectral data. Y it EXAMPLE 26Preparation of 5-amino-2-carbomethoxyarninobenzimidazole To 30 ml. offormic acid is cautiously added 0.5 g. of palladium catalyst (5% byweight on charcoal). Five grams of 5nitro-Z-carbomethoxyaminobenzimidazole" (Example 25) are dissolved in250 ml. of formic acid, which is then added cautiously to the catalystsuspension.

Preparation of 5-N,N-dimethylamino-Z-carbomethoxy benzimidazole2-Methyl-24hiopseudourea' sulfate (8.15 as previously described inExample'25. v

To the sulfate suspension isadded 9.34 g.' ((10986 moles) ofmethylchloroformate in one portion. To this mixture is added dropwise('17.55"cc.) of 25% aqueous sodium hydroxide, while maintaining thetemperature be low 20 C. When the NaOH" addition is completed, the pH ofthe mixture is about 7. The mixture is maintained below"20 C., and 7.15cc. of glacial acetic acid are added at a fairly rapid rate.

4- N,N-Dimethylamino -o-phenylenediamine "dihydro chloride (13.0 g.) isadded in one portion, and theresulting deep-purple mixture is thengradually heated'to is prepared 100 C. During the heating process,methyl merca'ptan' evolves which is routed through a series of threetraps, as-

until the-pH is 8.0. A lavender solid forms, which is filtered olf,washed liberally with water, and is dried on a porous plate overnight inthe air, yielding 9.0 g. of crude solid.

This solid is suspended in 350ccyof 1:1 ethanolwater, and treated with10% aqueous sodium hydroxide until .a solution, dark brown in color,forms. This is then treated with decolorizing Norit. A, filtered througha Su-' 7 per-Cel mat, and the dark filtrate is neutralized withglacial-acetic acid, togiveaalavender solid. 'This is collected, washedwith 1:1 ethanol-water, anddriedl on a porous plate in a steamoven,,giving a solid, m.p. 270- 276 C. (d.). i

This compound i-s; suspended in 1151 ethanol-water, and

sufiicient 10% sodium hydroxideadded tocause solution thereof. The darksolution is decolorized with Norit A,

filtered through a Super-Ce] mat, and the filtrate isneutralized to pH6.5 with glacial acetic acid giving a pinkish '2 solid, m.p. 250-275 "C.('d.)

This product is-suspended in 400cc. of 'ab out 20% aqueous ethanol.Sufficient glacial acetic acid is "added-to givethe solution a deepviolet 'co'lor. The solution is'decolorized with Norit fi 'and Darcotogether; Th'e'mi'xt'ure I is filtered through a 'Su'per-Cel mat,'*an'dthe filtrate is neu tralized to pH 6.5 with glacial aceticacid-'giving'a pinkish' solid, M.P. 250-275 C. (d.).

This product is :suspended in 400cc. of about 20% aqueousethanol.'='Sufiic-ient glacial acetic acid is added to give the solutiona deep violet color. The solution is de- .colorized with 'Norit'A and"Darcot ogether. The mixture is filteredgthrough a Super-Celmat, and thefiltrate is once again decolorized, again filtered througha Super Celthat,

and thenwthrough a Whatman'No. l"'gravity-'flutdpaper (torremovm anytraces of finely divided' charcoal):

The reaction mixture is put on a Parr shaker. for one" hour, duringwhich time 5 pounds of hydrogen are taken The final-filtrate is,neutralized'with 10% aqueous sodium hydroxide giving-a white solid,whichis filtered'oifiwashed with water, and dried overnight.

The compound; is suspended in 50%. aqueous ethanol; then.sufficient. 10%aqueous sodium hydroxide isi-added to Y give a solution which is againfiltered through asuper-Cel mat. The resulting clear light yellowfiltrate is-neutralized to., give awhite. solid, which is filtered off,washed w-ith 1 50% aqueous ethanol, and-dried. ina dessicatorover P 0 invacuo, giving .the pureproduct, 2336-2375 C.

The structure is confirmed by elemental analysis and spectral data.

28,403 17 18 We claim:

3,480,642 11/ 1969 Stedman 260-3092 1.5(6)-n-butyl-2-carbomethoxyaminobenzimidazole. 3,541,213 11/1970Klopping 260309.2 azZie5(6)-n-pr0p0xy 2 carbomethoxyaminobenzimid- OTHERREFERENCES References 5 Blor nquist et 3.1., V01. 56, pp. The followingreferences, cited by the Examiner, are Rldl et 4658.9 (1955) oitieliordin the patented file of this patent or the original HENRY LES, PrimaryExaminer p UNITED STATES PATENTS C. M. S. JAISLE, Assistant Examiner2,933,502 4/1960 Klopping 260-3092 10 2,933,504 4/1960 Klopping260-309.2 424 273 CL 3,010,968 11/1961 Loux 260309.2 2,920,994 1/ 1960Epperly et a1 424300

1. 5(6)-N-BUTYL-2-CARBOMETHOXYAMINOBENZIMIDAZOLE.